Esmolol, the methods for making and for treatment or prophylaxis of cardiac disorders using such compounds are disclosed in U.S. Pat. Nos. 4,387,103 and 4,593,119, incorporated herein by reference. Esmolol and its pharmaceutically acceptable salts, (e.g., hydrochloride salt) and related compounds have β-adrenergic blocking activity. It is a short-acting β-blocker, used in acute care settings to control the heart rate of a patient.
Esmolol is approved treating high blood pressure or rapid heart rate that occurs during or after surgery. It is also used in treating very rapid and irregular heart rates in emergency situations in particularly, atrial fibrillation, atrial flutter, or other similar irregular heart rhythms originating in the atria of the heart (the upper chambers). Under certain conditions some healthcare providers have administered Esmolol and other beta-blockers medication and/or prescribe as “off-label” uses for several coronary-imaging techniques including diagnosis of cardiac disease via medical imaging. The use of beta-blockers to reduce the heart rate that greatly influences and/or improves image quality and stenosis detection is well described (see for example, Ropers D et al. (2006) “Usefulness of multidetector row spiral computed tomography with 64×0.6-mm collimation and 330-ms rotation for the noninvasive detection of significant coronary artery stenoses”. Mollet N R et. al., “Multislice spiral computed tomography coronary angiography in patients with stable angina pectoris”. J Am Coll Cardiol (2004) 43:2265-2270, Nikolaou K et al. “Accuracy of 64-MDCT in the diagnosis of ischemic heart disease” (2006), Pugliese F et al. “Diagnostic accuracy of noninvasive 64-slice CT coronary angiography in patients with stable angina pectoris. Eur Radiol 16:575-582 Raff G L, Goldstein J. A. et. al. “Coronary angiography by computed tomography: coronary imaging evolves”. J Am Coll Cardiol. 2007 May 8; 49(18):1830); and other references. The current clinical practice for reducing or inducing lower heart rate to enable coronary computed tomography, quality coronary images is to prescribe long acting beta-blockers, oral medication of either Metroprolol or Atenolol of about 50-100 mg for several hour prior to the schedule procedures. Although, eventually the target heart rate of between 50 to 60 beat per minutes would be achieved by multiple combination of tablets and bolus injection of long acting beta-blockers, there are more drawbacks. Since most of these off-label uses are not based well designed clinical studies, the formulation, dosing regimen are also not designed to provided the optimal safety and effectiveness during such procedures. Current Esmolol premixed (vial and bag) presentations are not suitable for several coronary-imaging techniques due to the drawbacks of the formulation strength and dosing regimen of about 400 microgram per kilogram per minute which would maintain a heart rate of between 50 to 60 beat per minute for short procedures lasting between 0.5-1 hour) without heart fluctuation.
Esmolol hydrochloride {methyl3-[4-[2-hydroxy-3-(isopropylamino) propoxy]phenyl]propionate hydrochloride} is a water soluble molecule but would chemically decomposed via an acid/base catalyzed hydrolysis. The decomposition of Esmolol in aqueous environment is sole due to the labile aliphatic methyl ester group, that degrades into Esmolol acid free (also known as ASL-8123) {methyl3-[4-[2-hydroxy-3-(isopropylamino) propoxy]phenyl]propionic acid} and methanol. However, in some organic solvents and/or mixtures thereof, the rate of decomposition of Esmolol can be reduced, which was first disclosed in U.S. Pat. No. 5,017,609 and U.S. App. No. 20080293810. The concept of Premixed or Ready-to-use for Esmolol was first prepared for a concentrate from Brevibloc® 250 mg/mL, 10-mL ampoule presentation by Baaske, al. et., (see Baaske, D M. “Stability of esmolol hydrochloride in intravenous solutions.” Amer J of Hosp Pharmacy 51.21 (1994) pp 2693-6). The stability of admixture solutions of Esmolol Injection was limited to a few days in a PVC infusion bags. Escobar et. al., and Tiawari et. al., (see U.S. Pat. No. 5,017,609 and U.S. App. No. 20080293810) suggested that organic solvents have the ability of reducing the rate of degradation of Esmolol in co-solvent matrix. In 2007, Brevibloc® (Esmolol HCl) Injection, 250 mg/mL, 10-mL ampoule was withdrawn for the USA due solely to serious adverse events via medication errors. However, the chemical stability of Esmolol HCl and it compatibility to containers has proven to be very challenging for commercial viability due to its rapid decomposition in solutions. Several formulations of Esmolol HCl have been studied, with the degradation profile and the stability well characterized. However, the ability to aseptically, terminally sterilize by moist heat sterilization and/or other forms of sterilization of drugs in flexible plastic containers is still a “black box” especially co-solvent formulations with multiple instabilities and sterility issues.
Brevibloc® (Esmolol HCl) Injection, ready-to-use non-isotonic and isotonic formulations of Esmolol are disclosed in (U.S. Pat. Nos. 4,857,552, 6,310,094, 6,528,540, and U.S. App. No. 20080293814, 20100311738, Baaske, D M. “Stability of esmolol hydrochloride in intravenous solutions.” Amer J of Hosp Pharmacy 51.21 (1994): 2693-6, Rosenberg, L. S. et. al., “An accurate Prediction of the pH Change Due to Degradation: Correction for a “Produced” Secondary Buffering System.” Pharmaceutical Research 5.8 (1988): 514-517) packaged in either vial or plastic containers, respectively, incorporated herein by reference. In the prior art of the above mentioned references, the formulations of Esmolol in totally aqueous environment were stabilized via pH and self-buffering of the ASL-8123 {methyl3-[4-[2-hydroxy-3-(isopropylamino) propoxy]phenyl]propionic acid}. The rate of degradation of Esmolol hydrochloride in totally aqueous formulation is minimized by the concentration of Esmolol, buffer/self-buffering molecules within a near pH range. These formulations maintain a reasonable shelf-life, however, upon terminal sterilization in either in glass vials or flexible plastic, degradation occurs. As a result, prior art formulation package in vial (small volume parenteral) is prepared aseptically while the flexible plastic container (large volume parenteral) is terminally sterilized.
Currently, the commercialized products of Esmolol in the marketplace are these ready-to-use isotonic formulations in both flexible plastic and vial presentations. Lui et. al, taught that the ready-to-use isotonic formulations in containers were could be terminally sterilized, with significant decomposition. Further, larger volume parenteral injections are stored in IntraVia™ flexible plastic, a semi-free of PVC, such as those disclosed in U.S. Pat. Nos. 5,849,843 and 5,998,019 and are typically prefer by the national intravenous therapy association and regulatory authorities for being terminal sterilized. Terminal sterilization as a way of reducing microbiological burden and ensure patient safety of the finished product. However, not all drug formulations, and containers can withstand this technique of sterilization.
It is well known, described and documented in the pharmaceutical industry and any one skilled in the art of formulating co-solvent matrixes in medical plastics (flexible container or multi-layer plastic bags) are not compatible for long-storage due to multi-dimensional safety concerns. To name are few potential drawbacks; soften of the polymers, swallowing/collapse film materials, potential leachable (both drug and inks), drug incompatibility and deformation of the container closure system. Furthermore, for large volumes parenteral that require stricter microbiological controls and limits not to exacerbate cross-contaminations to already compromised patients, terminal sterilization is required. Multiple formulations of co-solvents, lipids, exotic encapsulations ranging from small molecules, large, lipophilic, hydrophobic, insoluble molecules, complex formulation with surface reducing agents, unstable drug substances, etc., have been stored for in medical plastic containers for small volume parenteral with major challenges. The exceptions to aforementioned are foods and cosmetics formulation that may not be suitable for injection and/or systemic circulation (drug delivery). An Intralipid formulation in flexible containers is worth noting, where perhaps different polymeric materials and process are used to claim sterility and non-cross microbiological contamination.
Liu et al. in U.S. Pat. Nos. 6,310,094 and 6,528,540 teach a heat sterilized esmolol formulation packaged in PVC bags. The patents all rely on the absence of ethanol and propylene glycol for success. Previous ready to use formulations had used both ethanol and propylene glycol as esmolol solubilizers. Prior formulations using these alcohols could not be successfully heat sterilized.
For over thirty years, Polyvinyl Chloride (PVC) flexible container and its shortcomings has been the commercial choose and the rate-limiting step for development of premixes in large volume parenteral injection. In recent past, the introduction of new flexible plastic container has improved, and issues of water loss, higher levels of extractables and port closure system integrity testing have been resolved. New flexible container material system and suitable port closures have be designed and more particularly, flexible autoclavable intravenous (IV) containers or bags of non-PVC polyolefin film (e.g., polyethylene or polypropylene) (polymeric materials are disclosed in U.S. Pat. Nos. 4,654,240, 5,849,843, 5,783,269, 5,998,019, 6,255,396, 6,461,696, and 6,590,033) nylon, or a composite material, either laminated or co-extruded structure (including both monolayer and multilayer structures). It is also possible to utilize bags composed of laminates where the inner laminate is inert to the solution such a bags with a polyolefin or polyethylene vinyl acetate (EVA). Non-PVC flexible plastic containers are considered to be relatively inert and contain low levels of extractable materials when subjected to aqueous or non-lipophillic drug substance/products. However, impart of co-solvents formulation, softness and deforms non-PVC films, leaching from the film and the heat sealed ports and closures becomes unacceptable for storage of certain pharmaceuticals. The non-PVC plastic films provides long shelf life for IV fluid containers, due to low moisture vapor transmission rate, and low levels extractables terminal sterilization using high temperature treatment, i.e., sterilized after filling to deactivate microorganisms inside the containers (e.g., autoclaving) are not suitable for all pharmaceutical formulations. Though, these new materials and technologies offered the pharmaceutical industry some flexibility in totally aqueous medias/formulations, additional US or European regulatory requirements on autoclave temperature, accumulative extractables for laminated or multilayer materials, administrative, injection ports and closure tips (systems) (polymeric materials/ports are disclosed in U.S. Pat. Nos. 4,778,697, 5,976300, 5,590,777, 6,869,653 and 7,207,157) have made it desirable for some pharmaceutical premixed to be designed in containers with lower moisture vapor transmission rate without the need for overwraps each container. The challenges facing premixed formulations are the long-term stability, the functionality of the complete assembled container/bag, and non-predicable adsorption and desorption for the longer term. All prior art for most of commercial flexible plastic container/bag has been focused totally aqueous formulations, while co-solvents, surfactants formulation or proteins are limited.
It is well known, characterized and well documented in literature and several patents that commercially available flexible plastic containers, both PVC, non-PVC plastic films are not compatible with certain drug substances due to their innate properties. Jenke, D. R. et. al., “Evaluation of model solvent systems for assessing the accumulation of container extractables in drug formulations” Int. J. Pharm. 224, 51-60; “Use of binary ethanol/water model solutions to mimic the interaction between a plastic material and pharmaceutical formulations” J. Appl. Polym. Sci. 89, 1049-1057; Thiesen, J. et. al. “physico-chemical stability of docetaxel premix solution and doxcetaxel infusion in PVC and polyolefine containers” Journal of Pharmacy World & Science, vol. 21, #3, June 1999, pp 137-141; Trissel L. A. et. al. “Handbook on Injectables drugs, 15th edition, Bethesda, Md.: American Society of Health-System Pharmacists, 2009; Moorhatch, P. et. al., “Interaction between drugs and plastic intravenous fluid bags. I sorption studies on 17 drugs.” Am. J. Hosp. Pharm. 31, 72-78; have used both PVC, non-PVC plastic films, and other plastic elastormers to show that there is a non-specific adsorption/desorption of drugs and drug matrixes from flexible plastic containers. Thus, formulations of drug substances in conjunction with drug matrixes such co-solvents and/or surfactants are not stable and they stability cannot be predicted in commercially available flexible plastic containers. Further, when these flexible plastic containers are stressed with delivery devices (i.e. sterilization via moist-heat processes), significant decomposition of the drug, deformity and leachables of the flexible plastic containers are detected.